How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

SIMPLE SUMMARY: Carriers of Lynch syndrome (LS) have an increased risk for several types of tumour, in particular bowel and uterine cancers. LS is caused by inheritance of a faulty mismatch repair (MMR) gene, and, in accordance with clinical guidelines, bowel cancers are tested for MMR deficiency to screen for LS. We review the significant barriers to following these guidelines in routine practice, and discuss guideline limitations. We also look at the advances in our knowledge and technology that may address some of these barriers and limitations. We further discuss additional LS screening strategies, in particular MMR deficiency testing of other tumour types and normal tissues to identify LS gene carriers. ABSTRACT: International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.